WO1990011283A1 - A process for the preparation of 9-substituted guanine derivatives and intermediates for use in the process - Google Patents
A process for the preparation of 9-substituted guanine derivatives and intermediates for use in the process Download PDFInfo
- Publication number
- WO1990011283A1 WO1990011283A1 PCT/DK1990/000077 DK9000077W WO9011283A1 WO 1990011283 A1 WO1990011283 A1 WO 1990011283A1 DK 9000077 W DK9000077 W DK 9000077W WO 9011283 A1 WO9011283 A1 WO 9011283A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- amino
- carboxamide
- imidazole
- thiocarbamoyl
- treatment
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical class O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 title claims abstract description 11
- 239000000543 intermediate Chemical class 0.000 title claims abstract description 6
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- -1 or R is (α) Chemical group 0.000 claims abstract description 12
- 229910001385 heavy metal Inorganic materials 0.000 claims abstract description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 6
- 238000010992 reflux Methods 0.000 claims abstract description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 5
- 125000000824 D-ribofuranosyl group Chemical group [H]OC([H])([H])[C@@]1([H])OC([H])(*)[C@]([H])(O[H])[C@]1([H])O[H] 0.000 claims abstract description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 5
- 239000002253 acid Substances 0.000 claims abstract description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical group [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 21
- QMYVMPRLRSVZBL-UHFFFAOYSA-N 4-(carbamothioylamino)-1h-imidazole-5-carboxamide Chemical class NC(=S)NC=1N=CNC=1C(N)=O QMYVMPRLRSVZBL-UHFFFAOYSA-N 0.000 abstract description 2
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 abstract 1
- 150000002500 ions Chemical class 0.000 abstract 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 35
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 29
- 229910052739 hydrogen Inorganic materials 0.000 description 24
- 239000000047 product Substances 0.000 description 22
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000000843 powder Substances 0.000 description 13
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 11
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 description 9
- 239000003245 coal Substances 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 7
- 229960004150 aciclovir Drugs 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- WDOYBEPLTCFIRQ-UHFFFAOYSA-N 2-amino-9-ethyl-3h-purin-6-one Chemical compound N1C(N)=NC(=O)C2=C1N(CC)C=N2 WDOYBEPLTCFIRQ-UHFFFAOYSA-N 0.000 description 4
- YBGIFRCRSMJOMZ-UHFFFAOYSA-N 5-(carbamothioylamino)-1-(2-hydroxyethoxymethyl)imidazole-4-carboxamide Chemical compound NC(=S)NC1=C(C(N)=O)N=CN1COCCO YBGIFRCRSMJOMZ-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 description 4
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 description 4
- 229940029575 guanosine Drugs 0.000 description 4
- 238000007363 ring formation reaction Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- KZYOKOLLHMHOLR-UHFFFAOYSA-N 1-benzyl-5-(carbamothioylamino)imidazole-4-carboxamide Chemical compound NC(=S)NC1=C(C(N)=O)N=CN1CC1=CC=CC=C1 KZYOKOLLHMHOLR-UHFFFAOYSA-N 0.000 description 3
- SCOKPTHVGOEBIW-UHFFFAOYSA-N 2-[(5-amino-4-carbamoylimidazol-1-yl)methoxy]ethyl acetate Chemical compound CC(=O)OCCOCN1C=NC(C(N)=O)=C1N SCOKPTHVGOEBIW-UHFFFAOYSA-N 0.000 description 3
- SMHBTBYHDWNJEG-UHFFFAOYSA-N 2-amino-9-benzyl-3h-purin-6-one Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1CC1=CC=CC=C1 SMHBTBYHDWNJEG-UHFFFAOYSA-N 0.000 description 3
- OSFDSLRVYKUBOP-UHFFFAOYSA-N 2-amino-9-propyl-3h-purin-6-one Chemical compound N1C(N)=NC(=O)C2=C1N(CCC)C=N2 OSFDSLRVYKUBOP-UHFFFAOYSA-N 0.000 description 3
- QTKYYXIZORIEEI-UHFFFAOYSA-N 5-(carbamothioylamino)-1-methylimidazole-4-carboxamide Chemical compound CN1C=NC(C(N)=O)=C1NC(N)=S QTKYYXIZORIEEI-UHFFFAOYSA-N 0.000 description 3
- DVNYTAVYBRSTGK-UHFFFAOYSA-N 5-aminoimidazole-4-carboxamide Chemical class NC(=O)C=1N=CNC=1N DVNYTAVYBRSTGK-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- CPEKAXYCDKETEN-UHFFFAOYSA-N benzoyl isothiocyanate Chemical compound S=C=NC(=O)C1=CC=CC=C1 CPEKAXYCDKETEN-UHFFFAOYSA-N 0.000 description 3
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- XMVONEAAOPAGAO-UHFFFAOYSA-N sodium tungstate Chemical compound [Na+].[Na+].[O-][W]([O-])(=O)=O XMVONEAAOPAGAO-UHFFFAOYSA-N 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- ZBNZAJFNDPPMDT-UHFFFAOYSA-N 1h-imidazole-5-carboxamide Chemical compound NC(=O)C1=CNC=N1 ZBNZAJFNDPPMDT-UHFFFAOYSA-N 0.000 description 2
- QURCXIIQSAIIAR-UHFFFAOYSA-N 5-(benzoylcarbamothioylamino)-1-benzylimidazole-4-carboxamide Chemical compound C=1C=CC=CC=1C(=O)NC(=S)NC1=C(C(=O)N)N=CN1CC1=CC=CC=C1 QURCXIIQSAIIAR-UHFFFAOYSA-N 0.000 description 2
- AIVZNYNMAVQYDV-UHFFFAOYSA-N 5-(benzoylcarbamothioylamino)-1-ethylimidazole-4-carboxamide Chemical compound CCN1C=NC(C(N)=O)=C1NC(=S)NC(=O)C1=CC=CC=C1 AIVZNYNMAVQYDV-UHFFFAOYSA-N 0.000 description 2
- ALUGLKCVKRCHSR-UHFFFAOYSA-N 5-(benzoylcarbamothioylamino)-1-propylimidazole-4-carboxamide Chemical compound CCCN1C=NC(C(N)=O)=C1NC(=S)NC(=O)C1=CC=CC=C1 ALUGLKCVKRCHSR-UHFFFAOYSA-N 0.000 description 2
- DRPRDPXASLIYCT-UUOKFMHZSA-N 5-(carbamothioylamino)-1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]imidazole-4-carboxamide Chemical compound NC(=S)NC1=C(C(N)=O)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 DRPRDPXASLIYCT-UUOKFMHZSA-N 0.000 description 2
- SECGBANTEUNXGO-UHFFFAOYSA-N 5-(carbamothioylamino)-1-[hydroxy(1-hydroxypropan-2-yloxy)methyl]imidazole-4-carboxamide Chemical compound OCC(C)OC(O)N1C=NC(C(N)=O)=C1NC(N)=S SECGBANTEUNXGO-UHFFFAOYSA-N 0.000 description 2
- NSXZKVSKOIMUKN-UHFFFAOYSA-N 5-(carbamothioylamino)-1-ethylimidazole-4-carboxamide Chemical compound CCN1C=NC(C(N)=O)=C1NC(N)=S NSXZKVSKOIMUKN-UHFFFAOYSA-N 0.000 description 2
- APLNCUAOMQJOIZ-UHFFFAOYSA-N 5-(carbamothioylamino)-1-propylimidazole-4-carboxamide Chemical compound CCCN1C=NC(C(N)=O)=C1NC(N)=S APLNCUAOMQJOIZ-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- SOIFLUNRINLCBN-UHFFFAOYSA-N ammonium thiocyanate Chemical compound [NH4+].[S-]C#N SOIFLUNRINLCBN-UHFFFAOYSA-N 0.000 description 2
- 150000001718 carbodiimides Chemical class 0.000 description 2
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- TUWDPWSZHGLVHH-UHFFFAOYSA-N (4,6-dimethoxy-1,3,5-triazin-2-yl)-(methoxymethyl)cyanamide Chemical compound COCN(C#N)C1=NC(OC)=NC(OC)=N1 TUWDPWSZHGLVHH-UHFFFAOYSA-N 0.000 description 1
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- YIWGJFPJRAEKMK-UHFFFAOYSA-N 1-(2H-benzotriazol-5-yl)-3-methyl-8-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carbonyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione Chemical compound CN1C(=O)N(c2ccc3n[nH]nc3c2)C2(CCN(CC2)C(=O)c2cnc(NCc3cccc(OC(F)(F)F)c3)nc2)C1=O YIWGJFPJRAEKMK-UHFFFAOYSA-N 0.000 description 1
- IMLPOIKFZQDSIW-UHFFFAOYSA-N 2-amino-9-[hydroxy(1-hydroxypropan-2-yloxy)methyl]-3h-purin-6-one Chemical compound N1C(N)=NC(=O)C2=C1N(C(O)OC(CO)C)C=N2 IMLPOIKFZQDSIW-UHFFFAOYSA-N 0.000 description 1
- BIPYIUKMNFPYHS-UHFFFAOYSA-N 5-(benzoylcarbamothioylamino)-1-methylimidazole-4-carboxamide Chemical compound CN1C=NC(C(N)=O)=C1NC(=S)NC(=O)C1=CC=CC=C1 BIPYIUKMNFPYHS-UHFFFAOYSA-N 0.000 description 1
- QFCCFUBHVTZGJS-UHFFFAOYSA-N 5-amino-1-[hydroxy(1-hydroxypropan-2-yloxy)methyl]imidazole-4-carboxamide Chemical compound OCC(C)OC(O)N1C=NC(C(N)=O)=C1N QFCCFUBHVTZGJS-UHFFFAOYSA-N 0.000 description 1
- JAODJMVGFQELNO-UHFFFAOYSA-N 5-amino-1-benzylimidazole-4-carboxamide Chemical compound NC1=C(C(=O)N)N=CN1CC1=CC=CC=C1 JAODJMVGFQELNO-UHFFFAOYSA-N 0.000 description 1
- WMRBKFPTMPNISL-UHFFFAOYSA-N 5-amino-1-ethylimidazole-4-carboxamide Chemical compound CCN1C=NC(C(N)=O)=C1N WMRBKFPTMPNISL-UHFFFAOYSA-N 0.000 description 1
- UZHKJZZQGXMAKP-UHFFFAOYSA-N 5-amino-1-methylimidazole-4-carboxamide Chemical compound CN1C=NC(C(N)=O)=C1N UZHKJZZQGXMAKP-UHFFFAOYSA-N 0.000 description 1
- LVONFJCKVYNYTJ-UHFFFAOYSA-N 5-amino-1-propylimidazole-4-carboxamide Chemical compound CCCN1C=NC(C(N)=O)=C1N LVONFJCKVYNYTJ-UHFFFAOYSA-N 0.000 description 1
- RTRQQBHATOEIAF-UHFFFAOYSA-N AICA riboside Natural products NC1=C(C(=O)N)N=CN1C1C(O)C(O)C(CO)O1 RTRQQBHATOEIAF-UHFFFAOYSA-N 0.000 description 1
- QZEGGZGLDILTQZ-UHFFFAOYSA-N CN1C=2N=C(NC(C2N=C1)=O)N.CN1C=2N=C(NC(C2N=C1)=O)N Chemical compound CN1C=2N=C(NC(C2N=C1)=O)N.CN1C=2N=C(NC(C2N=C1)=O)N QZEGGZGLDILTQZ-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- HEMHJVSKTPXQMS-DYCDLGHISA-M Sodium hydroxide-d Chemical compound [Na+].[2H][O-] HEMHJVSKTPXQMS-DYCDLGHISA-M 0.000 description 1
- RTRQQBHATOEIAF-UUOKFMHZSA-N acadesine Chemical compound NC1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 RTRQQBHATOEIAF-UUOKFMHZSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 150000001879 copper Chemical class 0.000 description 1
- BWFPGXWASODCHM-UHFFFAOYSA-N copper monosulfide Chemical compound [Cu]=S BWFPGXWASODCHM-UHFFFAOYSA-N 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N methyl mercaptane Natural products SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 1
- 230000001035 methylating effect Effects 0.000 description 1
- 125000000864 peroxy group Chemical group O(O*)* 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/052—Imidazole radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
Definitions
- the present invention relates to a process for the preparation of 9-substituted guanine derivatives of the general formula I
- guanosine can be prepared from 4-carboxamide-5-amino-1- ribofuranosyl imidazole by a process in three steps which involves condensation with carbodiimide derivatives, cyclization with PdO present and treatment with NH 4 OH.
- This process is not attractive because it requires use of the toxic compound phosgene to prepare the carbodiimide derivatives, and because the cyclization and the subsequent treatment with NH 4 OH take a very long time.
- the compound of formula I in which R is H can be prepared by a process in which the compound of formula II
- R has the same meaning as in formula I is cyclized a) by treatment with a heavy metal salt of the group of Cu-, Ag-, Pb- and Hg-salts in an aqueous alkaline medium containing at least four equivalents of OH- ions at a temperature from about 0°C to the reflux temperature, or b) by treatment with a peroxy compound in an aqueous alkaline medium at a temperature of about 0-30°C, whereafter I is isolated by treatment with acid and, if desired, is converted into a salt.
- R is C 1 -C 4 -alkyl optionally substituted with one or more hydroxy groups, or R is benzyl, ribosyl, 2'-deoxyribosyl or (CH 2 ) n -OR 1 , where n is 1 or 2, and R 1 is CH 2 CH 2 or
- the starting materials, of formula III can be prepared by reaction of 1-substituted 5-amino-1H-imidazole-4-carboxamides of the formula IV
- R has the same meaning as in formula I and in which hydroxyl groups, if any, in R may be acylated, with acylisothiocyanate and subsequent hydrolysis to remove the N-acyl group and any other acyl groups.
- the compounds of formula IV can be prepared by alkylation of the known compound 5-amino-1H-imidazole-4-carboxamide in a known manner.
- the process according to the invention in variant a) is preferably carried out using a copper salt as the heavy metal salt.
- a copper salt as the heavy metal salt.
- the process in variant a) is advantageously carried out in the way that the aqueous alkaline medium is provided with an alkali metal hydroxide, preferably sodium or potassium hydroxide.
- an alkali metal hydroxide preferably sodium or potassium hydroxide.
- the process according to the invention in variant b) is preferably carried out using hydrogen peroxide as the peroxy compound and in the presence of tungstate ions as a catalyst.
- 5-(N'-benzoylthiocarbamoyl)amino-1-ethyl-1H-imidazole-4- carboxamide was prepared in a similar manner from 5-amino- 1-ethyl-1H-imidazole 4-carboxamide, mp. 178-180°C.
- 5-(N'-benzoylthiocarbamoyl)amino-1-benzyl-1H-imidazole-4- carboxamide was prepared in a similar manner from 5-amino- 1-benzyl-1H-imidazole-4-carboxamide, mp. 181-182.5oC. 1-[(2-Hydroxyethoxy)methyl]-5-(thiocarbamoyl)amino-1H- imidazole-4-carboxamide.
- Acetyl chloride (1.6 g, 21 mM) was, under N 2 , added dropwise to a solution of ammonium thiocyanate (1.6 g, 21 mM) in acetone (30 ml) at 25oC in the course of 5 minutes. After reflux for 15 minutes it was cooled to 20oC, and the formed ammonium chloride was filtered off and washed with acetone (10 ml).
- 9-Ethylguanine was prepared in a similar manner from 1- ethyl-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide, mp. >300oC.
- 9-(1-Propyl)guanine was prepared in a similar manner from 1-(1-propyl)-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide, mp . >300oC. 13 C-NMR(DMSO-d 6 ) ⁇ ppm: 156.8; 153.3; 151.0; 137.4; 116.5; 44.2; 22.7; 10.8.
- Example 9 9 -Benzylguanine 1-Benzyl-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide (2.75 g, 10.0 mM) and sodium tungstate (0.1 g) were suspended in 6 N sodium hydroxide (20 ml) at 5oC. 35% hydrogen peroxide (4.0 ml, 44 mM) was added dropwise at 5-15oC over 30 minutes. Water (60 ml) was added to the resulting reaction mixture. After stirring for 1 hour in an ice bath pH was adjusted to 5 with hydrochloric acid. The formed product was filtered off, washed with water and dried. Hereby was isolated 1.30 g (54%) of the title compound as a white powder. HPLC indicated about 98% purity. The product had the same physical data as the product of example 4.
- 9-Methylguanine 9-Methylguanine was prepared In a similar manner from 1- methyl-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide. The product had the same physical data as the product of example 1.
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Abstract
A process for the preparation of 9-substituted guanine derivatives of general formula (I), in which R is C1-C4-alkyl optionally substituted with one or more hydroxy groups, or R is (α), benzyl, ribosyl, 2'-deoxyribosyl or (CH2)n-OR1 where n is 1 or 2, and R1 is CH¿2?CH2OH or (β) or salts thereof, in which a 1-substituted 5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide of general formula (III), where R has the same meaning as in formula (I), is cyclized: a) by treatment with a heavy metal salt of the group of Cu-, Ag-, Pb- and Hg-salts in an aqueous alkaline medium containing at least four equivalents of OH?-¿ions at a temperature from about 0°C to the reflux temperature, or b) by treatment with a peroxy compound in an aqueous alkaline medium at a temperature of about 0-30°C, whereafter (I) is isolated by treatment with acid and, if desired, is converted into a salt. The invention further comprises intermediates for use in the preparation of the above-mentioned compounds.
Description
Title: A process for the preparation of 9-substituted guanine derivatives and intermediates for use in the process .
Technical Field The present invention relates to a process for the preparation of 9-substituted guanine derivatives of the general formula I
or salts thereof. Compounds of this type are therapeutically active compounds having an antiviral activity or are intermediates for the preparation of compounds of interest in gene technology.
Background Art
It is known (J. Org. Chem. 51 1277-1282 (1986)) that guanosine can be prepared from 4-carboxamide-5-amino-1- ribofuranosyl imidazole by a process in three steps which involves condensation with carbodiimide derivatives, cyclization with PdO present and treatment with NH4OH. This process is not attractive because it requires use of the toxic compound phosgene to prepare the carbodiimide derivatives, and because the cyclization and the subsequent treatment with NH4OH take a very long time. It is also known that the compound of formula I in which R is H can be prepared by a process in which the compound of formula II
Disclosure of the Invention However, surprisingly we have found that it is possible to carry out cyclization of N1-substituted derivatives of compounds of formula II without methylating first and using a heavy metal salt in aqueous alkaline medium or
using peroxy compounds.
The process according to the invention is characterised in that a 1-substituted 5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide of the general formula III
III ,
where R has the same meaning as in formula I is cyclized a) by treatment with a heavy metal salt of the group of Cu-, Ag-, Pb- and Hg-salts in an aqueous alkaline medium containing at least four equivalents of OH- ions at a temperature from about 0°C to the reflux temperature, or b) by treatment with a peroxy compound in an aqueous alkaline medium at a temperature of about 0-30°C, whereafter I is isolated by treatment with acid and, if desired, is converted into a salt.
The starting compounds of formula III
III
in which R is C1-C4-alkyl optionally substituted with one or more hydroxy groups, or R is
benzyl, ribosyl, 2'-deoxyribosyl or (CH2)n-OR1, where n is 1 or 2, and R1 is CH2CH2 or
C or salts thereof
are novel compounds, and the invention therefore further comprises these compounds as intermediates for the preparation of 9-substituted guanine derivatives of formula I. The starting materials, of formula III can be prepared by reaction of 1-substituted 5-amino-1H-imidazole-4-carboxamides of the formula IV
IV,
in which R has the same meaning as in formula I and in which hydroxyl groups, if any, in R may be acylated, with acylisothiocyanate and subsequent hydrolysis to remove the N-acyl group and any other acyl groups.
The compounds of formula IV can be prepared by alkylation of the known compound 5-amino-1H-imidazole-4-carboxamide in a known manner.
Best Mode for Carrying out the Invention
The process according to the invention in variant a) is preferably carried out using a copper salt as the heavy
metal salt. Hereby a high yield is obtained with a cheap reagent.
Moreover, the process in variant a) is advantageously carried out in the way that the aqueous alkaline medium is provided with an alkali metal hydroxide, preferably sodium or potassium hydroxide.
The process according to the invention in variant b) is preferably carried out using hydrogen peroxide as the peroxy compound and in the presence of tungstate ions as a catalyst.
Preparation of starting materials
Preparation of 5-(N'-benzoylthiooarbamoyl)amino-1-methyl- 1H-imidazole-4-carboxamide
5-Amino-1-methyl-1H-imidazole-4-carboxamide (6.5 g, 45 mM) and benzoylisothiocyanate (7.7 g, 47 mM) were refluxed in acetone (90 ml) for 4 hours under N2. After cooling in an ice bath the formed product was filtered off, washed with acetone and dried. Hereby was isolated 13.0 g (95%) of the title compound as a white powder, mp 194-196ºC. 5-(N'-benzoylthiocarbamoyl)amino-1-ethyl-1H-imidazole-4- carboxamide was prepared in a similar manner from 5-amino- 1-ethyl-1H-imidazole 4-carboxamide, mp. 178-180°C.
5-(N'-benzoylthiocarbamoyl)amino-1-(1-propyl)-1H-imidazole- 4-carboxamide was prepared in a similar manner from 5- amino-1-(1-propyl)-1H-imidazole-4-carboxamide, mp. 163- 164ºC.
5-(N'-benzoylthiocarbamoyl)amino-1-benzyl-1H-imidazole-4- carboxamide was prepared in a similar manner from 5-amino- 1-benzyl-1H-imidazole-4-carboxamide, mp. 181-182.5ºC.
1-[(2-Hydroxyethoxy)methyl]-5-(thiocarbamoyl)amino-1H- imidazole-4-carboxamide.
5-Amino-1-[[2-(acetyloxy)ethoxy]methyl]-1H-imidazole-4- carboxamide (44.0 g, 182 mM) and benzoylisothiocyanate (29.7 g, 182 mM) were refluxed in acetone (430 ml) for 1 hour. To the resulting solution were added methanol (430 ml) and potassium carbonate (14.9 g, 108 mM) dissolved in water (45 ml) whereafter the mixture was refluxed for 4 hours. After cooling to room temperature acetic acid was added to a pH-value of 8. The formed product was filtered off at 0ºC, washed and dried. Hereby 39.2 g (83%) of the title compound was isolated as a white powder, mp. 181- 182ºC (dec.). A sample crystallized from water had mp. 182-183ºC (dec). 13C-NMR(DMSO-d6) δ ppm: 183.9; 163.7; 134.9; 129.3; 127.9; 74.0; 70.4; 59.7.
Calculated for C8H13N5O3S: C 37.06%, H 5.05%, N 27.01%,
S 12.37%
found: C 36.92%, H 5.07%, N 27.30%,
S 12.28%. 1- [1,3-Dihydroxy- (2-propyloxy)methyl]-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide was prepared in a similar manner from 5-amino-[1,3-dihydroxy-(2-propyloxy)methyl]-1H-imidazole-4-carboxamide, mp. 185ºC (dec.). 13C-NMR(DMSO-d6) δ ppm: 183.8; 163.9; 134.8; 129.2; 127.9; 80.2; 73.5; 60.7.
Calculated for C9H15N5O4S : C 37.36%, H 5.23%, N 24.21%,
S 11.08%
found: C 37.34%, H 5.16%, N 23.81%
S 10.76%. 1- [(2-Hydroxyethoxy)methyl]-5-(thiocarbamoyl)amino-1H- imidazole-4- carboxamide.
Benzoylchloride (5.9 g, 42 mM) was, under N2, added dropwise to a solution of ammoniumthiocyanate (3.2 g, 42 mM) in acetone (80 ml) at 25°C in the course of 5 minutes. After reflux for 15 minutes it was cooled to 20ºC, and the formed ammonium chloride was filtered off and washed with acetone (20 ml).
To the filtrate was added 5 -amino-1-[[2-(acetyloxy)ethoxy]methyl]-1H-imidazole-4-carboxamide (9.7 g, 40 mM). The mixture was refluxed under N2 for 90 minutes. Then methanol (80 ml) and potassium carbonate (5.8 g, 42 mM) dissolved in water (12 ml) were added and the mixture was refluxed for 8 hours under N2. Water (70 ml) was added to the hydrolysis mixture, and it was treated with activated coal at 25ºC. The solution was then evaporated to about 70 ml, and the pH-value adjusted to 7.0 with acetic acid. After cooling to 5ºC the resulting product was filtered off, washed with water and dried. Hereby was isolated 8.0 g (77%) of the title compound as a white powder, mp . 178- 180ºC (dec). HPLC indicated >96% purity. 1-[(2-Hydroxyethoxy)methyl]-5-(thiocarbamoyl)amino-1H- imidazole-4-carboxamide.
Acetyl chloride (1.6 g, 21 mM) was, under N2, added dropwise to a solution of ammonium thiocyanate (1.6 g, 21 mM) in acetone (30 ml) at 25ºC in the course of 5 minutes. After reflux for 15 minutes it was cooled to 20ºC, and the formed ammonium chloride was filtered off and washed with acetone (10 ml).
To the filtrate was added 5-amino-1-[[2-(acetyloxy)ethoxy]methyl]-1H-imidazole-4-carboxamide (4.8 g, 20 mM). The mixture was refluxed under N2 for 20 hours. Then methanol (40 ml) and potassium carbonate (5.8 g, 42 mM) dissolved in water (12 ml) were added and the mixture was
refluxed for 7 hours under N2. Water (50 ml) was added to the hydrolysis mixture, and it was treated with activated coal at 25ºC. The solution was then evaporated to about 30 ml and the pH-value adjusted to 7.0 with acetic acid. After cooling to 5ºC the formed product was filtered off, washed with water and dried. Hereby was isolated 3.2 g (62%) of the title compound as a white powder, mp . 175- 177ºC (dec). HPLC indicated >94% purity.
1-Methyl-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide. 5-(N'-benzoylthiocarbamoyl)amino-1-methyl-1H-Imidazole-4- carboxamide (12.1 g, 40 mM) was added to a mixture of acetone and methanol (1:1) (200 ml). Potassium carbonate 2.8 g, 20 mM) dissolved in water (12 ml) was added. The reaction mixture was refluxed under N2 for 6 hours where- after acetic acid (2.9 g, 48 mM) was added. After stirring in an ice bath the product was filtered off, washed and dried. Hereby was isolated 7.7 g (96%) of the title compound as a white powder, mp . 270-274ºC (dec.) (the conversion begins at about 220ºC). A sample crystallized from water melts at 280-283ºC (dec.) (the conversion begins at about 220ºC). C-NMR(DMSO-d6) δ ppm: 184.0, 163.9; 134,8; 130.2; 127.3; 30.9.
Calculated for C6H9N5OS: C 36.17%, H 4.55%, N 35.16% found: C 36.06%, H 4.53%, N 35.05% 1-Ethyl-5-(thiocarbamoyl)amino-1H-imidazol-4-carboxamide was prepared in a similar manner from 5-(N'-benzoylthiocarbamoyl)amino-1-ethyl-1H-imidazole-4-carboxamide, mp. 265-268ºC (dec.) 13C-NMR(DMSO-d6) δ ppm: 183.8; 163.9; 133.8; 129.1; 127.8; 39.0; 15,2. Calculated for C7H11N5OS: C 39.42%, H 5.20%, N 32.84% found: C 39.37%, H 5.19%, N 32.71%
1-(1-propyl)-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide was prepared in a similar manner from (5-(N'- benzoylthiocarbamoyl)amino-1-(1-propyl)-1H-imidazole-4- carboxamide, mp. 197-198°C (dec). 13C-NMR(DMSO-d6 ) δ ppm: 183.8; 163.9; 134.4; 129.2; 127.7; 45.7; 22.7; 10.8.
Calculated for C8H13N5OS: C 42.27%, H 5.77%, N 30.81% found: C 42.16%, H 5.84%, N 30.86%
1-Benzyl-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide was prepared in a similar manner from 5-(N'-benzoylthiocarbamoyl)amino-1-benzyl-1H-imidazole-4-carboxamide, mp . 264-266ºC (dec.) (the conversion begins at about 205°C) 13C-NMR(DMSO-d6) δ ppm: 183.8; 163.9; 136.5; 134.5; 129.6; 128.,6; 127 7; 127.4; 47.6.
Calculated for C12H13N5OS: C 52.34%, H 4.76%, N 25.44% found: C 52.31%, H 4.73%, N 25.52%
The following examples illustrate the process according to the invention. Examples 1-7 illustrate process variant a), and examples 8-12 illustrate process variant b).
Example 1 9 -Methylguanine
1-Methyl-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide (3.98 g, 20 mM) was dissolved in 1 N sodium hydroxide (160 ml). Copper acetate, H2O (4.6 g, 23 mM) was addec. and the reaction mixture was then refluxed for 1 hour. After cooling to 50ºC the formed copper sulphide was filtered off. The filtrate was acidified with acetic acid to pH 5.0. The resulting product was filtered off at 25ºC, washed with water and dried. Hereby was isolated 3.16 g (96%) of the title compound as a white powder, mp. >300ºC. 13C-NMR(1N NaOD) δ ppm: 170.7; 163.6; 154.0, 141.4; 120.0;
32 . 2 .
Calculated for C6H7N5O: C 43.63%, H 4.27%, N 42.41% found: C 43.05%, H 4.20%, N 41.95%
Example 2 9-Ethylguanine
9-Ethylguanine was prepared in a similar manner from 1- ethyl-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide, mp. >300ºC.
Calculated for C7H9N5O, 1/4H2O: C 45.77%, H 5.21%, N 38.13% found: C 45.52%, H 5.00%, N 38.04%
Example 3
9-(1-Propyl)guanine
9-(1-Propyl)guanine was prepared in a similar manner from 1-(1-propyl)-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide, mp . >300ºC. 13C-NMR(DMSO-d6) δ ppm: 156.8; 153.3; 151.0; 137.4; 116.5; 44.2; 22.7; 10.8.
Calculated for C8H11N5O: C 49.73%, H 5.74%, N 36.25.% found: C 49.50%, H 5.76%, N 36.30%
Example 4 9-Benzylguanine
9-Benzylguanine was prepared in a similar manner from 1- benzyl-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide, mp. 305-308ºC. 13C-NMR(DMSO-d6) δ ppm: 157.0; 153.8; 151.2; 137.6; 137.3; 128.7; 127.6; 127.2; 116.6; 45.9.
Calculated for C12H11N5O: C 59.74%, H 4.59%, N 29.03% found: C 59.50%, H 4.51%, N 28.91%
Example 5a
9-[(2-Hydroxyethoxy)methyl]guanine (Acyclovir) 1-[2-Hydroxyethoxy)methyl]-5-(thiocarbamoyl)amino-1H- imidazole-4-carboxamide (10.0 g, 38.6 mM) was added to a suspension of copper sulphate (7.0 g, 44 mM) in 6 N sodium hydroxide (80 ml) and was stirred at room temperature for 4 hours. HPLC indicated 100% yield. After filtration 50% aqueous acetic acid (80 ml) was added to the filtrate. After a brief period of reflux the material was cooled to 5ºC. The product was filtered off and crystallized from water, treatment being made with activated coal. Hereby was isolated 7.8 g (85%) 9 -[(2-hydroxyethoxy)methyl] guanine, 3/4 H2O (Acyclovir) as a white powder. HPLC indicated >99% purity, mp. about 250ºC (dec.) 13C-NMR(DMSO- d6) δ ppm: 156.8; 153.8; 151.4; 137.8; 116.5; 72.1; 70.4 and 59.9.
Calculated for C8H11N5O3, 3/4 H2O: C 40.25%, H 5.28%,
N 29.34%
found: C 40.39%, H 5.22%,
N 29.37%.
Example 5b
9-[(2-Hydroxyethoxy)methyl)guanine (Acyclovir). 1-[(2-Hydroxyethoxy)methyl]-5-(thiocarbomoyl)amino-1H- imidazole-4-carboxamide (1.30 g, 5.0 mM) was added to a suspension of copper acetate, H2O (1.15g, 5.75 mM) in 1 N sodium hydroxide (60 ml) and refluxed for 30 minutes. HPLC indicated 100% yield. After filtration acetic acid (5 ml) was added to the filtrate, and then heating with
activated coal was performed. The coal was filtered off, whereafter the material was cooled to 5°C. The precipitated product was filtered off, washed with water and dried. Hereby was isolated 0.92 g (77%) of 9-[(2-hydroxy- ethoxy)methyl]guanine, 3/4 H2O as a white powder. HPLC indicated >99% purity.
The use of other heavy metal salts and varying amounts of sodium hydroxide in the process of example 5 is illustrated by the following table.
Preparation of Acyclovir
1-[(2-Hydroxyethoxy)methyl]
5-(thiocarbamoyl)amino-1H- Acyclovir imidazole-4-carboxamide
9 -[1,3-Dihydroxy-(2-prooyloxy)methyl]guanine
1-[1,3-Dihydroxy-(2-propyloxy)methyl]-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide (0.58 g, 2.0 mM) was added to a suspension of copper sulphate (0.32 g, 2.3 mM) in 3 N sodium hydroxide (8 ml) and refluxed for 1 hour. HPLC indicated 100% yield. After filtration 33% aqueous acetic acid (6 ml) was added to the filtrate, and it was refluxed again while being treated with activated coal. The coal was filtered off and the solution was cooled to 5ºC. Filtration, washing with water and drying resulted in 0.33 g (61%) of 9-[1,3-dihydroxy-(2-propyloxy)methyl]guanine, 3/4 H2O as a white powder, mp . about 245°C (dec.).13C-NMR(DMSO-d6) δ ppm: 157.0; 153.9; 151.3; 137.6; 116.3; 79.9; 71.4; 60.8.
Calculated for C9H13H5O4, 3/4 H2O: C 40.22%, H 5.43%,
N 26.06%
found: C 40.25%, H 5.31%,
N 25.58% Example 7
9-β-D-Ribofuranosyl guanine (guanosine)
5-Amino-1-( β-D-ribofuranosyl)-1H-Imidazole-4-carboxamide (5.0 g, 19.4 mM) and benzoylisothiocyanate (3.3 g, 20 mM) was stirred at room temperature in DMF (40 ml) for 1 hour. The solvent was stripped off in water-jet vacuo. The residue was dissolved in methanol (160 ml) and potassium carbonate (1.6 g, 11.6 mM) in water (8 ml) was added whereafter the mixture was refluxed for 2 hours. After cooling to room temperature acetic acid was added to pH 6. The reaction mixture was evaporated in water-jet vacuo, and the residue was crystallized from ethanol. Hereby was isolated 5.0 g of crude 1-(β-D-ribofuranosyl)-5-(thio
carbamoyl)amino-1H-imidazole-4-carboxamide. HPLC indicated a purity of about 65% (the remaining 35% was essentially potassium acetate).
The crude product of 1-(β-D-ribofuranosyl)-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide (5.0 g) was added to a suspension of copper sulphate (2.9 g, 18 mM) in 3 N sodium hydroxide (60 ml) and refluxed for 1 hour. After filtration 33% aqueous acetic acid (30 ml) was added to the filtrate and it was refluxed again while being treated with activated coal. The coal was filtered off, and the solution was cooled to room temperature overnight. Filtration, washing with water and drying gave 2.0 g (65%) of 9-β-D-ribofuranosyl guanine, H2O (guanosine, H2O) as a white powder, mp. 250ºC (dec.). The product had the same physical data as an authentic sample of guanosine, H2O.
Example 8
9-(1-Propyl)guanine
1-(1-Propyl)-5-thiocarbamoyl)amino-1H-imidazole-4-carboxamide (1.14 g, 5.0 mM) and sodium tungstate (0.2 g) were dissolved in 1 N sodium hydroxide (50 ml) at 0ºC. 35% hydrogen peroxide (1.8 ml, 20 mM) in water (5 ml) was added dropwise at 0-10ºC in the course of 30 minutes. After stirring in an ice bath for 1 hour pH was adjusted to 5 with acetic acid. The formed product was filtered off, washed with water and dried. Hereby was isolated 0.41 g (42%) of the title compound as a white powder. HPLC indicated >98% purity. The product had the same physical data as the product of example 3.
Example 9 9 -Benzylguanine
1-Benzyl-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide (2.75 g, 10.0 mM) and sodium tungstate (0.1 g) were suspended in 6 N sodium hydroxide (20 ml) at 5ºC. 35% hydrogen peroxide (4.0 ml, 44 mM) was added dropwise at 5-15ºC over 30 minutes. Water (60 ml) was added to the resulting reaction mixture. After stirring for 1 hour in an ice bath pH was adjusted to 5 with hydrochloric acid. The formed product was filtered off, washed with water and dried. Hereby was isolated 1.30 g (54%) of the title compound as a white powder. HPLC indicated about 98% purity. The product had the same physical data as the product of example 4.
Example 10
9-Methylguanine 9-Methylguanine was prepared In a similar manner from 1- methyl-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide. The product had the same physical data as the product of example 1.
Example 11 9-Ethylguanine
9-Ethylguanine was prepared in a similar manner from 1- ethyl-5-(thiocarbamoyl)amino-1-imidazole-4-carboxamide. The product had the same physical data as the product of example 2. Example 12
9-T(2-Hydroxyethoxy)methyl]guanine (Acyclovir)
1-[(2-Hydroxyethoxy)methyl]-5-(thiocarbamoyl)amino-1H- imidazole-4-carboxamide (2.59 g, 10.0 mM) and sodium
tungstate (0.05 g) were dissolved in 6 N sodium hydroxide (20 ml) at 5ºC. 35% hydrogen peroxide (4.0 ml, 44mM) was added dropwise at 5-15ºC in the course of 15 minutes. After stirring for 15 minutes at 0-5ºC HPLC indicated 59% yield of the title compound. The pH-value of the reaction mixture was adjusted to 5.5 with 25% aqueous acetic acid. The resulting product was filtered off, washed with water and dried which gave 1.13 g (50%) of the title compound as a white powder. HPLC indicated a purity of about 97%. The product had the same physical data as the product of example 5.
Claims
1. A process for the preparation of 9-substituted guanine derivatives of the general formula I
I, 
in which R is C1-C4-alkyl, optionally substituted with one or more hydroxy groups, or R is
benzyl, ribosyl, 2'-deoxyribosyl or (CH2)n-OR1 where n is 1 or 2, and R1 is CH2CH2OH or CH OH 
and salts thereof,
c h a r a c t e r i s e d in that a 1-substituted 5- (thiocarbamoyl)amlno-1H-imldazole-4-carboxamide of the general formula III
III, 
where R has the same meaning as in formula I is cyclized a) by treatment with a heavy metal salt of the group of Cu-, Ag-, Pb- and Hg-salts in an aqueous alkaline medium containing at least four equivalents of OH- ions at a temperature from about 0ºC to the reflux temperature, or b) by treatment with a peroxy compound in an aqueous alkaline medium at a temperature of about 0-30ºC, whereafter I is isolated by treatment with acid and, if desired, is converted into a salt.
2. A process as claimed in claim 1 a), c h a r a c¬t e r i s e d in that the heavy metal salt is a copper salt.
3. A process as claimed in claim 1 b), c h a r a c t e r i s e d in that the peroxy compound is hydrogen peroxide, and the reaction is preferably carried out in the presence of tungstate ions as a catalyst.
4. Intermediates for use in the preparation of guanine compounds of the general formula (I) as claimed in claim 1, c h a r a c t e r i s e d in that they are 1-substituted5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamides of the general formula III
H2NOC
III ,
in which R is C1-C4-alkyl optionally substituted with one or more hydroxy groups, or R is 
benzyl, ribosyl, 2'-deoxyribosyl or (CH2)n-OR1 where n is 1 or 2, and R1 is CH2CH2OH or 2
or salts thereof, 
Priority Applications (12)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| BR909007230A BR9007230A (en) | 1989-03-20 | 1990-03-19 | PROCESS FOR THE PREPARATION OF 9-SUBSTITUTED GUANINE DERIVATIVES AND INTERMEDIARIES FOR USE IN THE PROCESS |
| DE69013146T DE69013146T2 (en) | 1989-03-20 | 1990-03-19 | METHOD FOR PRODUCING 9-SUBSTITUTED GUANINE DERIVATIVES AND INTERMEDIATE PRODUCTS FOR USE IN THE METHOD. |
| RU9093004872A RU2090566C1 (en) | 1989-03-20 | 1990-03-19 | Method of synthesis 9-substituted guanine derivatives |
| KR1019910701187A KR0142098B1 (en) | 1989-03-20 | 1990-03-19 | Process for preparing 9-substituted guanine derivatives and intermediates for use in the methods |
| RO148411A RO109737B1 (en) | 1989-03-20 | 1990-03-19 | 9-substituted guanine derivates preparation process and intermediaries preparation process therefor |
| EP90905442A EP0464112B1 (en) | 1989-03-20 | 1990-03-19 | A process for the preparation of 9-substituted guanine derivatives and intermediates for use in the process |
| FI914418A FI97387C (en) | 1989-03-20 | 1991-09-19 | Process for the preparation of 9-substituted guanine derivatives and intermediates for use in the process |
| SU915001705A RU2042668C1 (en) | 1989-03-20 | 1991-09-19 | Method of synthesis of 9-substituted guanine derivatives and 1-substituted 5-(thiocarbamoyl) -amino-1h- imidazole-4- carboxamides |
| NO913686A NO178497C (en) | 1989-03-20 | 1991-09-19 | Process for the preparation of 9-substituted guanine derivatives and intermediates for use in the process |
| BG95145A BG60590B1 (en) | 1989-03-20 | 1991-09-20 | Method for the preparation of 9-substituted quanine derivatives |
| LVP-92-250A LV10455B (en) | 1989-03-20 | 1992-12-02 | A process for the preparation of 9-substituted guanine derivatives and intermediates for use in the process |
| GEAP19931494A GEP19971014B (en) | 1989-03-20 | 1993-08-25 | Process for the preparation of 9-substituted guanine derivatives and intermediates for use in the process |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK1354/89 | 1989-03-20 | ||
| DK135489A DK135489D0 (en) | 1989-03-20 | 1989-03-20 | PROCEDURE FOR THE PREPARATION OF 9-SUBSTITUTED GUANINE DERIVATIVES AND INTERMEDIATES FOR USING THE PROCEDURE |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1990011283A1 true WO1990011283A1 (en) | 1990-10-04 |
Family
ID=8103930
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/DK1990/000077 WO1990011283A1 (en) | 1989-03-20 | 1990-03-19 | A process for the preparation of 9-substituted guanine derivatives and intermediates for use in the process |
Country Status (28)
| Country | Link |
|---|---|
| US (1) | US5223619A (en) |
| EP (1) | EP0464112B1 (en) |
| KR (1) | KR0142098B1 (en) |
| AR (1) | AR245719A1 (en) |
| AT (1) | ATE112568T1 (en) |
| BG (1) | BG60590B1 (en) |
| BR (1) | BR9007230A (en) |
| CA (1) | CA2047217A1 (en) |
| CS (1) | CS275359B2 (en) |
| DD (1) | DD293116A5 (en) |
| DE (1) | DE69013146T2 (en) |
| DK (2) | DK135489D0 (en) |
| ES (1) | ES2061023T3 (en) |
| FI (1) | FI97387C (en) |
| GE (1) | GEP19971014B (en) |
| GR (1) | GR1001096B (en) |
| HR (1) | HRP920907B1 (en) |
| HU (1) | HU206715B (en) |
| IE (1) | IE62042B1 (en) |
| LT (1) | LT3183B (en) |
| LV (1) | LV10455B (en) |
| NO (1) | NO178497C (en) |
| PL (1) | PL163313B1 (en) |
| RO (1) | RO109737B1 (en) |
| RU (2) | RU2090566C1 (en) |
| SI (1) | SI9010545A (en) |
| WO (1) | WO1990011283A1 (en) |
| YU (1) | YU47343B (en) |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997012887A1 (en) * | 1995-10-05 | 1997-04-10 | Chiroscience Limited | Purine and guanine derivatives as pnp inhibitors |
| US6761758B2 (en) | 2002-09-04 | 2004-07-13 | Xerox Corporation | Alkylated tetrakis(triaminotriazine) compounds and phase change inks containing same |
| US6811595B2 (en) | 2002-09-04 | 2004-11-02 | Xerox Corporation | Guanidinopyrimidinone compounds and phase change inks containing same |
| US6860928B2 (en) | 2002-09-04 | 2005-03-01 | Xerox Corporation | Alkylated urea and triaminotriazine compounds and phase change inks containing same |
| US6872243B2 (en) | 2002-09-04 | 2005-03-29 | Xerox Corporation | Phase change inks containing gelator additives |
| US7144450B2 (en) | 2004-12-04 | 2006-12-05 | Xerox Corporation | Phase change inks containing trans-1,2-cyclohexane bis(urea-urethane) compounds |
| US7153349B2 (en) | 2004-12-04 | 2006-12-26 | Xerox Corporation | Phase change inks containing curable trans-1,2-cyclohexane bis(urea-urethane) compounds |
| US7220300B2 (en) | 2004-12-04 | 2007-05-22 | Xerox Corporation | Phase change inks containing bis(urea-urethane) compounds |
| US7314949B2 (en) | 2004-12-04 | 2008-01-01 | Xerox Corporation | Trans-1,2-cyclohexane bis(urea-urethane) compounds |
| US7317122B2 (en) | 2004-12-04 | 2008-01-08 | Xerox Corporation | Curable trans-1,2-cyclohexane bis(urea-urethane) compounds |
| US7560587B2 (en) | 2004-12-04 | 2009-07-14 | Xerox Corporation | Bis[urea-urethane] compounds |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1264599B1 (en) * | 1993-06-14 | 1996-10-04 | Solar Chem Sa | PROCESS FOR THE SYNTHESIS OF 9- (2-IDROSSIETOSSIMETIL) - GUANINA |
| CA2338305A1 (en) * | 1998-07-23 | 2000-02-03 | Fujisawa Pharmaceutical Co., Ltd. | Imidazole compounds |
| EP3062949B2 (en) | 2013-10-29 | 2023-05-24 | SWEP International AB | A method of brazing a plate heat exchanger using scren printed brazing material |
| CN115504977B (en) * | 2022-09-23 | 2024-02-09 | 海南锦瑞制药有限公司 | Preparation method of ganciclovir and preparation method of ganciclovir for injection |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0126813A1 (en) * | 1983-05-24 | 1984-12-05 | Newport Pharmaceuticals International, Inc. | Process for preparing imidazole compounds |
| EP0219838A2 (en) * | 1985-10-22 | 1987-04-29 | Takeda Chemical Industries, Ltd. | Carbocyclic purine nucleosides, their production and use |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS56152437U (en) * | 1980-04-14 | 1981-11-14 | ||
| US4451478A (en) * | 1982-03-12 | 1984-05-29 | Newport Pharmaceuticals International, Inc. | Imidazole compounds |
| US4602089A (en) * | 1982-03-12 | 1986-07-22 | Newport Pharmaceuticals, Inc. | Process for preparing purine compounds |
| JPS6055071B2 (en) * | 1982-04-16 | 1985-12-03 | 四国化成工業株式会社 | Imidazolyl succinic acid compound and epoxy resin curing method using the compound |
| MY101126A (en) * | 1985-12-13 | 1991-07-31 | Beecham Group Plc | Novel compounds |
-
1989
- 1989-03-20 DK DK135489A patent/DK135489D0/en not_active Application Discontinuation
-
1990
- 1990-03-16 IE IE99490A patent/IE62042B1/en unknown
- 1990-03-19 BR BR909007230A patent/BR9007230A/en not_active Application Discontinuation
- 1990-03-19 CA CA002047217A patent/CA2047217A1/en not_active Abandoned
- 1990-03-19 DK DK90905442.1T patent/DK0464112T3/en active
- 1990-03-19 KR KR1019910701187A patent/KR0142098B1/en not_active Expired - Fee Related
- 1990-03-19 DE DE69013146T patent/DE69013146T2/en not_active Expired - Fee Related
- 1990-03-19 HU HU902874A patent/HU206715B/en not_active IP Right Cessation
- 1990-03-19 AT AT90905442T patent/ATE112568T1/en not_active IP Right Cessation
- 1990-03-19 EP EP90905442A patent/EP0464112B1/en not_active Expired - Lifetime
- 1990-03-19 RU RU9093004872A patent/RU2090566C1/en active
- 1990-03-19 RO RO148411A patent/RO109737B1/en unknown
- 1990-03-19 WO PCT/DK1990/000077 patent/WO1990011283A1/en active IP Right Grant
- 1990-03-19 US US07/761,890 patent/US5223619A/en not_active Expired - Fee Related
- 1990-03-19 ES ES90905442T patent/ES2061023T3/en not_active Expired - Lifetime
- 1990-03-20 CS CS901365A patent/CS275359B2/en unknown
- 1990-03-20 PL PL90284379A patent/PL163313B1/en unknown
- 1990-03-20 GR GR900100212A patent/GR1001096B/en unknown
- 1990-03-20 AR AR90316421A patent/AR245719A1/en active
- 1990-03-20 SI SI9010545A patent/SI9010545A/en unknown
- 1990-03-20 DD DD90338906A patent/DD293116A5/en not_active IP Right Cessation
- 1990-03-20 YU YU54590A patent/YU47343B/en unknown
-
1991
- 1991-09-19 FI FI914418A patent/FI97387C/en active
- 1991-09-19 RU SU915001705A patent/RU2042668C1/en active
- 1991-09-19 NO NO913686A patent/NO178497C/en unknown
- 1991-09-20 BG BG95145A patent/BG60590B1/en unknown
-
1992
- 1992-10-02 HR HRP-545/90A patent/HRP920907B1/en not_active IP Right Cessation
- 1992-12-02 LV LVP-92-250A patent/LV10455B/en unknown
-
1993
- 1993-01-27 LT LTIP297A patent/LT3183B/en not_active IP Right Cessation
- 1993-08-25 GE GEAP19931494A patent/GEP19971014B/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0126813A1 (en) * | 1983-05-24 | 1984-12-05 | Newport Pharmaceuticals International, Inc. | Process for preparing imidazole compounds |
| EP0219838A2 (en) * | 1985-10-22 | 1987-04-29 | Takeda Chemical Industries, Ltd. | Carbocyclic purine nucleosides, their production and use |
Non-Patent Citations (2)
| Title |
|---|
| J.Chem.Soc.Perkin Trans.1, 1987, C.B. REESE et al: "The conversion of the 2',3'-0-isopropylidene derivative of 5-amino-1-D-ribofuranosylimidazole-4-carboxami-de(AICA riboside) into 2',3'-0-isopropylidene-isoquanosine", see page 1527 - page 1531. * |
| Nucleic Acids Research, Vol. 3, No. 1, 1986 A YAMAZAKI et al: "Synthesis of guanosine and its derivatives from 5-amino-1-beta-D-ribofuranolsyl-4-imidazolecar-boxamide. IV. A new route to guanosine via cyanamide derivative. 1,2", see page 251 - page 259. * |
Cited By (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5912252A (en) * | 1995-10-05 | 1999-06-15 | Darwin Discovery Limited | Purine and guanine derivatives as PNP inhibitors |
| WO1997012887A1 (en) * | 1995-10-05 | 1997-04-10 | Chiroscience Limited | Purine and guanine derivatives as pnp inhibitors |
| US7371858B2 (en) | 2002-09-04 | 2008-05-13 | Xerox Corporation | Guanidinopyrimidinone compounds and phase change inks containing same |
| US6761758B2 (en) | 2002-09-04 | 2004-07-13 | Xerox Corporation | Alkylated tetrakis(triaminotriazine) compounds and phase change inks containing same |
| US6811595B2 (en) | 2002-09-04 | 2004-11-02 | Xerox Corporation | Guanidinopyrimidinone compounds and phase change inks containing same |
| US6835833B2 (en) | 2002-09-04 | 2004-12-28 | Xerox Corporation | Alkylated tetrakis(triaminotriazine) compounds and phase change inks containing same |
| US6860928B2 (en) | 2002-09-04 | 2005-03-01 | Xerox Corporation | Alkylated urea and triaminotriazine compounds and phase change inks containing same |
| US6872243B2 (en) | 2002-09-04 | 2005-03-29 | Xerox Corporation | Phase change inks containing gelator additives |
| US7087752B2 (en) | 2002-09-04 | 2006-08-08 | Xerox Corporation | Alkylated urea and triaminotriazine compounds and phase change inks containing same |
| US7504502B2 (en) | 2002-09-04 | 2009-03-17 | Xerox Corporation | Guanidinopyrimidinone compounds and phase change inks containing same |
| US7157601B2 (en) | 2002-09-04 | 2007-01-02 | Xerox Corporation | Alkylated urea and triaminotriazine compounds and phase change inks containing same |
| US7144450B2 (en) | 2004-12-04 | 2006-12-05 | Xerox Corporation | Phase change inks containing trans-1,2-cyclohexane bis(urea-urethane) compounds |
| US7314949B2 (en) | 2004-12-04 | 2008-01-01 | Xerox Corporation | Trans-1,2-cyclohexane bis(urea-urethane) compounds |
| US7317122B2 (en) | 2004-12-04 | 2008-01-08 | Xerox Corporation | Curable trans-1,2-cyclohexane bis(urea-urethane) compounds |
| US7220300B2 (en) | 2004-12-04 | 2007-05-22 | Xerox Corporation | Phase change inks containing bis(urea-urethane) compounds |
| US7153349B2 (en) | 2004-12-04 | 2006-12-26 | Xerox Corporation | Phase change inks containing curable trans-1,2-cyclohexane bis(urea-urethane) compounds |
| US7560587B2 (en) | 2004-12-04 | 2009-07-14 | Xerox Corporation | Bis[urea-urethane] compounds |
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